PATH-73. Cholesterol metabolism in esophageal cancer brain metastases: insights from RNA sequencing analysis

BACKGROUND The prognosis for patients with esophageal cancer remains poor, and the disease continues to be a leading cause of cancer-related mortality worldwide. Esophageal brain metastasis, although rare (0.3% to 3.8%), is associated with significantly worse outcomes. The molecular mechanisms driving brain metastasis in esophageal cancer are poorly understood. This study aimed to characterize transcriptional differences between esophageal cancer patients with and without brain metastasis. We hypothesized that using RNA sequencing would enable the identification of targetable pathways that contribute to brain metastasis in patients with esophageal adenocarcinoma. METHODS Pre-chemoradiation (CRT) and post-CRT tumor samples were macro-dissected from patients with (n = 3) and without (n = 23) brain metastasis to conduct bulk RNA sequencing. Aligned reads were mapped to the human reference genome (hg38), and differential gene expression (≥2-fold, P ≤ 0.05) was assessed using the DESeq2 package in Partek Flow. Pathway analysis was performed using Ingenuity Pathway Analysis (IPA). RESULTS A total of 1,607 differentially expressed genes (DEGs) were identified, including 1,325 downregulated and 282 upregulated genes in tumor samples from patients with brain metastasis. Pathway analysis using IPA revealed activation of cholesterol biosynthesis pathways, driven by the upregulation of genes such as CYP51A1, EBP, HMGCS1, and MVD. It also predicted activation of Sterol Regulatory Element-Binding Proteins, key regulators of cholesterol metabolism. CONCLUSION Previous studies have suggested a link between cholesterol biosynthesis and cancer progression. Our RNA sequencing findings further support this association and emphasize the potential role of cholesterol metabolism in metastatic behavior in esophageal adenocarcinoma. Future laboratory and prospective studies should investigate the activation of these genes to assess their potential as biomarkers for metastatic risk.